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Culture Documents
2013, 4 (7)
www.irjponline.com
Research Article
INTRODUCTION
Codeine (Figure 1) is a narcotic analgesic drug, which is used
in the alleviation of minor to moderate pain and as an
antitussive. Its pharmaceutical preparations (analgesic tablets,
capsules and antitussive syrups) are subject to abuse1 and are
sometimes used, in large doses, by heroin addicts to obtain a
rewarding effect or to justify the presence of morphine,
resulting from heroin, in their urine2. Codeine is prepared
either by the methylation of morphine or extraction from the
natural product opium3. During routine confirmation of
immunoassay-opiate-positive urine by GC-MS, we had
detected the opium alkaloid thebainone-A (Figure 2) in the
urine of codeine pharmaceutical preparation users. In
investigative experiments designed to trace the source of
thebainone-A in those preparations, aqueous solutions of
codeine at different pH values were exposed to sunlight or
kept in the dark and then analyzed by GC-MS. Thebainone-A
was not detected in any of the test solutions, however, other
compounds were, differing in nature according to the pH of
the solutions and the presence or absence of photo effects.
The main aim of this study was to characterize those
compounds and investigate their possible formation in
aqueous pharmaceutical preparations as they might be a
source of toxicity. Furthermore, as opium forms an important
source of codeine, it will be investigated for codeine-related
products that might have been formed during processing and
storage.
MATERIALS AND METHODS
Materials
Reference standard of codeine phosphate was a kind gift from
Pharmacare Pharmaceuticals, Dubai, UAE. Opium samples
were obtained as seizures submitted to our laboratory by the
Drug Enforcement Department of Sharjah Police (UAE).
Syrups containing codeine, pseudoephedrine and triprolidine
Page 49
OH
C H 3O
Abundance
TIC: CODPHN_1.D
2800000
2600000
2400000
2200000
2000000
1800000
codeine
1600000
1400000
1200000
1000000
800000
600000
norcodeine
400000
200000
0
6.00
7.00
8.00
9.00
10.00
11.00
Codeinone
12.00
13.00
Time-->
14.00
15.00
Abundance
Scan 1239 (12.304 min): CODPHN_1.D
297
40000
35000
30000
25000
20000
42
15000
190
10000
240
115
81
5000
128
99
55
40
60
165
80
100
120
140
228
212
254
178
140
68
0
152
160
180
200
220
240
260
268
282
280
300
m/z-->
Figure 3: A: Total ion chromatogram obtained from a neutral-pH solution of codeine exposed to sunlight or in dark.
Page 50
Abundance
Ion 315.00 (314.70 to 315.70): CODPH1_1.D
300000
280000
260000
240000
220000
200000
180000
160000
140000
120000
100000
80000
60000
II
40000
20000
0
6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
Time-->
Abundance
Scan 1354 (12.973 min): CODPH1_1.D
315
300000
280000
260000
44
240000
220000
112
200000
180000
160000
140000
120000
100000
126
80000
70
60000
40000
83
57
0
40
189
162
96
20000
60
80
100
120
204
239
139
140
160
258
225
175
180
200
286
272
220
240
260
280
298
300
320
m/z-->
Abundance
Scan 1419 (13.351 min): CODPH1_1.D
44
315
110000
100000
90000
112
80000
70000
60000
II
50000
40000
30000
70
189
20000
94
10000
204
162
128
239
146
258
40
60
80
100
120
140
160
180
200
220
298
282
223
0
240
260
280
387
300
320
340
360
380
m/z-->
Figure 4: A: Ion chromatogram at m/z 315, obtained from aqueous acidic-pH solution of codeine exposed to sunlight
B and C: Mass spectra of compounds I and II as per labels
Abundance
III
400000
350000
300000
250000
200000
150000
IV
100000
50000
0
6.00
7.00
8.00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
17.00
Time-->
B
III
Page 51
73
600000
550000
500000
450000
196
400000
459
350000
300000
250000
200000
150000
94
100000
256
234
50000
0
40
60
80
100
120
370
171
129
55
152
140
160
180
200
220
260
280
431
342
294
240
402
312
275
216
300
320
340
360
380
400
420
440
460
m/z-->
Abundance
Scan 1454 (13.400 min): HOCOD_2.D
73
550000
500000
450000
196
400000
350000
459
300000
250000
200000
150000
100000
94
256
234
50000
0
129
55
40
60
80
100
120
171
152
140
275
216
160
180
200
220
240
260
280
300
402
370
312
431
342
294
320
340
360
380
400
420
440
460
m/z-->
Figure 5: A: Extractedion chromatogram at m/z 459, obtained from aqueous acidic-pH solution of codeine exposed to sunlight
B and C: Mass spectra of compounds III and IV as per labels. The GC-MS analysis was carried out after TMS derivatization
Abundance
Ion 459.00 (458.70 to 459.70): OPNEO2.D
300000
280000
260000
240000
220000
200000
180000
160000
140000
120000
100000
80000
60000
40000
20000
6.00
7.00
8.00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
Time-->
Abundance
Scan 1263 (12.444 min): OPNEO2.D
229
800000
700000
600000
500000
400000
73
459
300000
200000
370
100000
45
0
50
103
100
164
132
150
188
207
200
254
250
328
284
309
300
350
350
403
400
431
450
m/z-->
Figure 6: A: Extractedion chromatogram at m/z 459, obtained from TMS-derivatized basic-pH extract of opium.
B: mass spectrum of the compound V
Page 52
16
C o d e in e
M W
= 299
C H
9
14
11
a u t o x id a t io n
( a c id ic s o lu t io n ,
s u n lig h t )
15
7
13
12
3
17
10
O H
o x id a t io n
( n e u t r a l s o lu t io n )
N - d e m e t h y la t io n
( n e u t r a l o r b a s ic s o lu t io n )
N C H
N H
C H
C H
O H
N C H
H O
N o r c o d e in e
M W = 285
C o d e in o n e
M W = 297
N C H
H O
+
C H
C H
O H
M W
M W
O H
A lp h a - 1 0 - h y d r o x y c o d e in e
B e t a - 1 0 - h y d r o x y c o d e in e
= 315
o f d i- T M S d e r iv a t iv e = 4 5 9
5.
6.
7.
8.
9.
10.
11.
12.
13.
Page 54